A critical role for PKR complexes with TRBP in immunometabolic regulation and eIF2α phosphorylation in obesity

Takahisa Nakamura, Ryan C. Kunz, Cai Zhang, Taishi Kimura, Celvie L. Yuan, Brenna Baccaro, Yuka Namiki, Steven P. Gygi, Gökhan S. Hotamisligil

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading toPKRactivation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2α phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease.

Original languageEnglish
Pages (from-to)295-307
Number of pages13
JournalCell Reports
Volume11
Issue number2
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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